Adrenergic Blockers

INTRODUCTION
Adrenergic blockers are also called as antiadrenergic drugs or sympatholytics.
Adrenergic blocking agents prevent the response of effector organs to
endogenous as well as exogenous adrenaline and noradrenaline. These drugs
block the actions of adrenergic drugs at alpha (α) or beta (β) adrenergic
receptors.

Many types of adrenergic antagonists are used and several of these are clinically
useful in medicine, particularly in the treatment of cardiovascular diseases.
Drugs that decrease the amount of norepinephrine released as a consequence of
sympathetic nerve stimulation as well as drugs that inhibit sympathetic nervous
activity by suppressing sympathetic outflow is also widely used in medications.
Almost all of these agents are competitive antagonists in their interactions with
either α or β adrenergic receptors, and one exception is phenoxybenzamine, an
irreversible antagonist that binds covalently to α-adrenergic receptors. These are
due to important structural differences among the various types of adrenergic
receptors. Selective β antagonist drugs are used to act on the heart and selective
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β antagonist drugs are used to act on the respiratory system.

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PHYSIOLOGICAL BASIS OF ADRENERGIC RECEPTOR

ANTAGONISTS
Blockade of vasoconstrictor α receptors reduces peripheral resistance and
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causes reduced cardiac output leads to decreased blood pressure. The α blockers
abolish the pressor action of adrenaline, which then produces fall in the blood
pressure due to β mediated vasodilatation called Dale’s vasomotor reversal.
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Pressor action of selective α-agonists is suppressed. Reflex tachycardia occurs

due to the presynaptic α receptors.
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Nasal stuffness and miosis result due to the blockade of α receptors. The
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therapeutic application of drugs coming under the adrenergic antagonists are

receptor oriented, especially β blockers are used as antihypertensive, α
adrenergic antagonists are used to control the peripheral vascular resistance.

Mechanism of Action of α-Adrenergic Blockers

α-Adrenergic receptor response in clinical relevance include α receptor 2

mediated contraction of arterial and venous smooth muscle. α adrenergic

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receptors are involved in suppressing sympathetic output, increasing vagal tone,
facilitating platelet aggregation, inhibiting the release of norepinephrine, and
acetylcholine from nerve endings. Blockade of α receptors inhibits
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vasoconstriction induced by endogenous catecholamines. Vasodilatation may

occur in both arteriolar resistance vessels and veins. α receptor regulates both
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central and peripheral sympathetic neurons. Acceleration of presynaptic α

receptors inhibits the norepinephrine release. In some vascular beds, these drugs
promote vasodilatation through the release of nitric oxide (endothelial relaxing
factor). Phenoxybenzamine inhibits the uptake of catecholamine from the nerve
terminals. Phentolamine and tolazoline are competitive α adrenergic antagonists
and block the receptor for 5-HT and it causes the release of histamine from the
mast cells, which is a potent vasodilator.

Mechanism of Action of β-Adrenergic Receptor Blockers

β adrenergic receptor antagonists slow the heart rate and decrease the
myocardial contractility, these prolongs the systolic conduction and disturbs the
ventricular fibres. Dimensions of the ventricle is decreased, oxygen
consumption is decreased, and thereby decreases the heart rate and aortic
pressure. In blood vessels, these drugs reduces the noradrenaline release from
the sympathetic terminals and decrease the renin from kidney due to the
blockade of β receptors.

CLASSIFICATION
I. Alpha receptor blocking agents

a. Beta halo alkyl amines

i. Dibenamine
ii. Phenoxy benzamine

b. Natural and dehydrogenated ergot alkaloids

c. Imidazole derivatives

d. Quinazolines
e. Miscellaneous 
Indoramine 

Yohimbine 

Chlorpromazine

II. Beta-receptor blocking agents

a. β-Blockers with membrane stabilizing activity and intrinsic
sympathomimetic property

i. Oxprenalol

ii. Pindalol

b. Specific β-blockers
i. Timolol

ii. Nodalol
c. β-blockers with membrane stabilizing activity
i. Propranolol

d. β-blockers with cardio selective action

i. Acebutolol

ii. Atenolol

iii. Metaprolol
iv. Esmolol

e. β-Blockers with α-blocking property

i. Labetolol

ii. Carvediol
Alpha-receptor blocking agents

i. Phenoxybenzamine
Structure

Mechanism of action: Phenoxybenzamine produces its therapeutic actions by

blocking alpha receptors, leading to a muscle relaxation and a widening of the
blood vessels. This widening of the blood vessels results in a lowering of blood
pressure.

Uses: Irreversible antagonist with nonselective actions, a major use of

phenoxybezamine is in the treatment of pheochromocytoma (tumours of the
adrenal medulla). It is used to treat peripheral vascular diseases, such as
Raynaud’s syndrome. It has also been used in the case of shock and frostbite to
improve blood flow to peripheral tissues. Used in the treatment of shock and in
the treatment of pulmonary oedema.

ii. Tolazoline
Structure

Synthesis

From: Phenyl acetonitrile

Mechanism of action: Vasodilation by means of a direct effect on peripheral
vascular smooth muscle and indirect effects produced, in part, by release of
endogenous histamine; tolazoline has moderate alpha-adrenergic blocking
activity and has histamine agonist activity. Tolazoline usually reduces
pulmonary arterial pressure and vascular resistance.

Uses: It is an imidazolidine derivative. It is a competitive alpha adrenergic

antagonist and possesses similar affinity for α and α receptors. It is a
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vasodilator and has a sympathomimetic effect to stimulate the heart and causes
mydriasis. It is of some use in the treatment of Raynaud’s disease, cerebral
vascular accidents. It has been used in the treatment of persistent pulmonary
hypertension of the newborn.

iii. Phentolamine
Structure

Mechanism of action: Phentolamine produces its therapeutic actions by

competitively blocking alpha-adrenergic receptors (primarily excitatory
responses of smooth muscle and exocrine glands), leading to a muscle
relaxation and a widening of the blood vessels. This widening of the blood
vessels results in a lowering of blood pressure. The action of phentolamine on
the alpha adrenergic receptors is relatively transient and the blocking effect is
incomplete. The drug is more effective in antagonizing responses to circulating
epinephrine and/or norepinephrine than in antagonizing responses to mediator
released at the adrenergic nerve ending. Phentolamine also stimulates β-
adrenergic receptors and produces a positive inotropic and chronotropic effect
on the heart and increases cardiac output.
Uses: Phentolamine is a nonselective α-adrenoreceptor antagonist with an
immediate onset and short duration of action. In addition to α-blocking activity,
it has weak muscarnic activity in the gastrointestinal tract and weak to mild
histaminergic activity in the stomach. It is an α-adrenergic blocker used in
urgent heart failure. Used as an aid for the diagnosis of pheochromocytoma, and
may be administered immediately prior to or during pheochromocytomectomy
to prevent or control paroxysmal hypertension resulting from anesthesia, stress,
or operative manipulation of the tumor. Phentolamine has also been used to
treat hypertensive crisis caused by sympathomimetic amines or catecholamine
excess by certain foods or drugs in patients taking MAO inhibitors, or by
clonidine withdrawal syndrome.

iv. Prazosin
Structure

Mechanism of action: Alpha-adrenergic receptors are essential for the

regulation of blood pressure in humans. Two types of alpha receptors, alpha 1
and alpha 2, both play a role in regulating blood pressure. Alpha-1 receptors are
postsynaptic (located after the nerve junction, or space between a nerve fiber
and target tissue). In this case, the target tissue is the vascular smooth muscle.
These receptors, when activated, increase blood pressure.Prazosin inhibits the
postsynaptic alpha-1 adrenoceptors. This inhibition blocks the vasoconstricting
(narrowing) effect of catecholamines (epinephrine and norepinephrine) on the
vessels, leading to peripheral blood vessel dilation. Through blood vessel
constriction by adrenergic receptor activation, epinephrine and norepinephrine
normally act to increase blood pressure.

Uses: A selective α-antagonist, prazosin, reduces peripheral vascular resistance

and lowers arterial blood pressure in both supine and erect patients. Dizziness,
headache, and palpitations can occur. Used to treat hypertension of any degree.
It has been used in decreasing cardiac overload. This drug is indicated for the
treatment of hypertension (high blood pressure). Prazosin can be given alone or
given with other blood pressure-lowering drugs, including diuretics or beta-
adrenergic blocking agents. Prazosin does not negatively impact lung function,
and therefore may be used to manage hypertension in patients who are
asthmatic or patients with chronic obstructive lung disease (COPD).
v. Dihydroergotamine
Structure

Mechanism of action: Two theories have been proposed to explain the efficacy
of 5-HT1D receptor agonists in migraine: 1) activation of 5-HT1D receptors
located on intracranial blood vessels, including those on arterio-venous
anastomoses, leads to vasoconstriction, which correlates with the relief of
migraine headache and 2) activation of 5-HT 1D receptors on sensory nerve
endings of the trigeminal system results in the inhibition of pro-inflammatory
neuropeptide release.

Uses: For the acute treatment of migraine headaches with or without aura and
the acute treatment of cluster headache episodes.

v. Methysergide
Structure
Mechanism of action: Methysergide is serotonin antagonists acts on central
nervous system (CNS), which directly stimulates the smooth muscle leading to
vasoconstriction. Some alpha-adrenergic blocking activity has been reported.
Suggestions have been made by investigators as to the mechanism whereby
Methysergide produces its clinical effects, but this has not been finally
established, although it may be related to the antiserotonin effect.

Uses: For the treatment of vascular headache.

Beta receptor blocking agents

i. Propranolol
Structure

Synthesis
Mechanism of action: Propranolol is a nonselective β-adrenergic receptor
antagonist.2 Blocking of these receptors leads to vasoconstriction, inhibition of
angiogenic factors like vascular endothelial growth factor (VEGF) and basic
growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells,
as well as down regulation of the renin-angiotensin-aldosterone system.

Uses: It is a nonselective β-adrenergic antagonist and it has equal affinity for β1

and β receptors. Propranolol is also indicated to treat angina pectoris due to

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coronary atherosclerosis, atrial fibrillation, myocardial infarction, migraine,

essential tremor, hypertrophic subaortic stenosis, pheochromocytoma, and
proliferating infantile hemangioma.

ii. Atenolol
Structure

Mechanism of action: Atenolol is a cardioselective beta-blocker, called such

because it selectively binds to the β1-adrenergic receptor as an antagonist up to
a reported 26 fold more than β2 receptors.15 Selective activity at the β1 receptor
produces cardioselectivity due to the higher population of this receptor in
cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at
therapeutic dosages but the effects mediated by antagonizing these are
significantly reduced from those of non-selective agents. β1 and β2 receptors
are Gs coupled therefore antagonism of their activation reduces activity of
adenylyl cyclase and its downstream signalling via cyclic adenosime
monophosphate and protein kinase A (PKA).

Uses: It is a β selective drug with low lipid solubility. Mainly used in the
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treatment of essential hypertension. Used for management of angina pectoris

associated with coronary atherosclerosis. Used for management of acute
myocardial infarction in hemodynamically stable patients with a heart rate
greater than 50 beats per minutes and a systolic blood pressure above 100
mmHg.
iii. Metipranolol
Structure

Mechanism of action: Although it is known that metipranolol binds the beta1

and beta2 adrenergic receptors, the mechanism of metipranolol's action is not
known. It has no significant intrinsic sympathomimetic activity, and has only
weak local anesthetic (membrane-stabilizing) and myocardial depressant
activity. It appears that the ophthalmic beta-adrenergic blocking agents reduce
aqueous humor production, as demonstrated by tonography and
fluorophotometry. A slight increase in aqueous humor outflow may be an
additional mechanism.

Uses: Indicated in the treatment of elevated intraocular pressure in patients with

ocular hypertension or open angle glaucoma.

iv. Betaxolol
Structure

Mechanism of action: Betaxolol selectively blocks catecholamine stimulation

of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This
results in a reduction of heart rate, cardiac output, systolic and diastolic blood
pressure, and possibly reflex orthostatic hypotension. Betaxolol can also
competitively block beta(2)-adrenergic responses in the bronchial and vascular
smooth muscles, causing bronchospasm.

Uses: Used for the management of hypertension.

 vi. Bisoprolol
Structure

Mechanism of action: Though the mechanism of action of bisoprolol has not

been fully elucidated in hypertension, it is thought that therapeutic effects are
achieved through the antagonism of β-1adrenoceptors to result in lower cardiac
output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist.
When β1-receptors (located mainly in the heart) are activated by adrenergic
neurotransmitters such as epinephrine, both the blood pressure and heart rate
increase, leading to greater cardiovascular work, increasing the demand for
oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the
need for oxygen through competitive inhibition of β1-adrenergic receptors.
Bisoprolol is also thought to reduce the output of renin in the kidneys, which
normally increases blood pressure. Additionally, some central nervous system
effects of bisoprolol may include diminishing sympathetic nervous system
output from the brain, decreasing blood pressure and heart rate.
Uses: Bisoprolol is indicated for the treatment of mild to moderate
hypertension. It may be used off-label to treat heart failure, atrial fibrillation,
and angina pectoris.
vi.Esmolol
Structure

Mechanism of action: Similar to other beta-blockers, esmolol blocks the

agonistic effect of the sympathetic neurotransmitters by competing for receptor
binding sites. Because it predominantly blocks the beta-1 receptors in cardiac
tissue, it is said to be cardioselective. In general, so-called cardioselective beta-
blockers are relatively cardioselective; at lower doses they block beta-1
receptors only but begin to block beta-2 receptors as the dose increases. At
therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity
(ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity
is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In
the Vaughan Williams classification of antiarrhythmics, beta-blockers are
considered to be class II agents.

Uses: Used for the rapid control of ventricular rate in patients with atrial
fibrillation or atrial flutter in perioperative, postoperative, or other emergent
circumstances where short term control of ventricular rate with a short-acting
agent is desirable. Also used in noncompensatory sinus tachycardia where the
rapid heart rate requires specific intervention.

vii. Metoprolol
Structure

Mechanism of action: Metoprolol is a beta-1-adrenergic receptor inhibitor

specific to cardiac cells with negligible effect on beta-2 receptors. This
inhibition decreases cardiac output by producing negative chronotropic and
inotropic effects without presenting activity towards membrane stabilization nor
intrinsic sympathomimetics.

Uses: Metoprolol is indicated for the treatment of angina, heart failure,

myocardial infarction, atrial fibrillation, atrial flutter and hypertension.

viii. Labetolol
Structure
Mechanism of action: Labetalol non-selectively antagonizes beta-adrenergic
receptors, and selectively antagonizes alpha-1-adrenergic receptors. Antagonism
of beta-1-adrenergic receptors leads to a slight decrease in heart
rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects
of labetalol such as bronchospasms, however this may be slightly attenuated by
alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over
the long term without a significant decrease in cardiac output or stroke volume,
and a minimal decrease in heart rate.

Uses: It is the mixture that is used clinically in treating hypertension. The

different isomers, however, posses different α and β-antagonistic activities.

ix. Carvedilol
It acts on both β and α-adrenergic receptors. Only δ isomer is β–blocking, and
both enantiomers have α-blocking activity.

Structure

Mechanism of action: Carvedilol inhibits exercise induce tachycardia through

its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic
receptors relaxes smooth muscle in vasculature, leading to reduced peripheral
vascular resistance and an overall reduction in blood pressure. At higher doses,
calcium channel blocking and antioxidant activity can also be seen. The
antioxidant activity of carvedilol prevents oxidation of low density lipoprotein
and its uptake into coronary circulation.

Uses: Used in treating hypertension and congestive heart failure. Carvedilol is

indicated to treat mild to severe heart failure, left ventricular dysfunction after
myocardial infarction with ventricular ejection fraction ≤40%, or hypertension.

STRUCTURE-ACTIVITY RELATIONSHIP
Propranolol has become one of the most thoroughly studied and widely used
drug in the therapeutic armamentarium; it is the standard against which all other
β antagonists are compared.

 The aromatic ring and its substituent is the primary determinant of β 1

antagonistic activity. The aryl group also affects the absorption, excretion,
and metabolism of the β blockers.
 β blockers are structurally similar to β agonist. The catechol ring can be
replaced by a variety of ring system without loss of antagonistic activity.
 Replacement of catechol hydroxyl group with chlorine of phenyl ring
system retains β blocking activity. Example: pronethalol,
dichloroisoproterenol.
 N, N–disubstitution decreases the β blocking activity, and the activity is
maintained when the phenyl ethyl, hydroxy phenyl ethyl, or methoxy phenyl
ethyl groups are added to amine as a part of the molecule.
 The two carbon chains are essential for activity.
 The introduction of –OCH group into the molecule between the aromatic
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ring and the ethyl amine side chain provides β blocking agents, for example,
propranolol.
 As in the sympathomimetics, bulky aliphatic groups, such as the tert-
butyl and isopropyl groups are normally found on the amino function of the
aryloxypropanolamine β receptor antagonists. It must be a secondary amine
for optimal activity.
 As with the sympathomimetic agents, the configuration of the hydroxyl
bearing carbon of the aryloxypropanolamine side chain play a critical role in
the interaction of β antagonist drugs with β receptor. The carbon must
possess the (S) configuration for optimal affinity to the β receptor. The
enantiomer with the (R) configuration is typically 100 times less potent.